Pericytes Derived from Adipose-Derived Stem Cells Protect against Retinal Vasculopathy

Abstract

BackgroundRetinal vasculopathies, including diabetic retinopathy (DR), threaten the vision of over 100 million people. Retinal pericytes are critical for microvascular control, supporting retinal endothelial cells via direct contact and paracrine mechanisms. With pericyte death or loss, endothelial dysfunction ensues, resulting in hypoxic insult, pathologic angiogenesis, and ultimately blindness. Adipose-derived stem cells (ASCs) differentiate into pericytes, suggesting they may be useful as a protective and regenerative cellular therapy for retinal vascular disease. In this study, we examine the ability of ASCs to differentiate into pericytes that can stabilize retinal vessels in multiple pre-clinical models of retinal vasculopathy.Methodology/Principal FindingsWe found that ASCs express pericyte-specific markers in vitro. When injected intravitreally into the murine eye subjected to oxygen-induced retinopathy (OIR), ASCs were capable of migrating to and integrating with the retinal vasculature. Integrated ASCs maintained marker expression and pericyte-like morphology in vivo for at least 2 months. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented retinal capillary dropout (53% reduction). Treatment of ASCs with transforming growth factor beta (TGF-β1) enhanced hASC pericyte function, in a manner similar to native retinal pericytes, with increased marker expression of smooth muscle actin, cellular contractility, endothelial stabilization, and microvascular protection in OIR. Finally, injected ASCs prevented capillary loss in the diabetic retinopathic Akimba mouse (79% reduction 2 months after injection).Conclusions/SignificanceASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple murine models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with TGF-β1 treatment, as seen with native retinal pericytes. ASCs may represent an innovative cellular therapy for protection against and repair of DR and other retinal vascular diseases.

Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics

“…Our data are consistent with the growing body of evidence of the pivotal roles of pericytes and pericyte-like cells in modulating microvascular physiology and function (2,6,10,12,13,38,49,70). For example, when adipose-derived stem cells, which can be shifted to a pericyte-like phenotype with TGF-␤ pretreatment, are delivered intravitreally, prevention of vascular dropout or microvascular stabilization can be achieved (45). Ultimately, we predict a physiological-pathological spectrum of pericyte contractility, which either maintains vascular stability and CEC quiescence or fosters an angiogenic activation response downstream of mechanical alterations.…”

Adipose-derived stem cells increase angiogenesis through matrix metalloproteinase-dependent collagen remodeling

“…Consistent with previous reports, the increased expression of α-SMA by ASCs was not driven by HUVEC-secreted factors, but required direct cell-cell contact between both cell types 30,39 . Yet it is also possible that ASCs intrinsically expressing α-SMA migrated toward the endothelial cells and contributed to increased pericyte coverage 40 . In addition to inhibiting endothelial sprouting, pericytes are critical to basement membrane assembly, of which type IV collagen represents an important component 32 .…”

Mesenchymal Stem Cell Therapy in Type 1 Diabetes Mellitus and Its Main Complications: From Experimental Findings to Clinical Practice

“…MSCs could thus have a great impact on DR treatment since they can act as immunomodulatory agents and reactive oxygen species (ROS) scavengers [98]. Furthermore, due to striking similarities between MSCs and pericytes, MSCs might replace the latter, thereby compensating for pericyte loss [99]; Mendel et al, and Rajashekhar et al, have shown that adipose-derived MSCs intravitreally injected into diabetic mice were able to migrate and integrate into the retinal vasculature, leading to microvascular stabilisation and a marked reduction in capillary dropout [100,101].…”